Not applicable.
This invention relates to methods of measuring nuclear magnetic resonance characteristics of nuclei generally, and, in particular to a method of determining the spin-spin relaxation time (T2) of nuclei using spin echoes and for utilizing the T2 relaxation time to aid in detection of mental disorders including but not limited to attention-deficit/hyperactivity disorder (ADHD).
As is known in the art, magnetic resonance imaging (MRI) (aka nuclear magnetic resonance or NMR) is a form of medical imaging in which the data is displayed as images which are presented in the form of individual slices that represent planar sections of objects. The data in the images represents the density and bonding of protons (primarily in water) in the tissues of the body, based upon the ability of certain atomic nuclei in a magnetic field to absorb and re-emit electromagnetic radiation at certain frequencies.
As is also known, MRI is based on the magnetic properties of atomic nuclei with odd numbers of protons or neutrons, which exhibit magnetic properties because of their spin. The predominant source of magnetic resonance signals in the human body is hydrogen nuclei or protons. In the presence of an external magnetic field these hydrogen nuclei align along the axis of the external magnetic field and can precess or wobble around that field direction at a definite frequency known as the Larmor frequency.
The magnetic resonance effects occur when nuclei in a static magnetic field H are excited by a rotating magnetic field H1 in the x, y plane resulting in a total vector M given by M=Hz+H1 (x cos w0t+y sin w0t). Upon cessation of the excitation, the magnetic field decays back to its original alignment with the static field H, emitting electromagnetic radiation at the Larmor frequency which can be detected by the same coil which produced the excitation.
One method for imaging utilizes a transmit/receive coil to emit a magnetic field at frequency f0 which is the Larmor frequency of plane P. Subsequently, magnetic gradients are applied in the y and x directions Gx, Gy for times tx, ty. A signal is detected in a data collection window over the period of time for which a magnetic gradient Gx is applied.
The detected signal S(tx, ty) can be expressed as a two-dimensional Fourier transform of the magnetic resonance signal s(x,y) with u="Ugr"Gxtx/2xcfx80, v="Ugr"Gyty/2xcfx80. The magnetic resonance signal s(x,y) depends on the precise sequence of pulses of magnetic energy used to perturb the nuclei.
For a typical sequence known as spin-echo the detected magnetic resonance signal can be expressed
s(x,y)=xcfx81(1xe2x88x92exe2x88x92tr/T1)(exe2x88x92tr/T2)
where xcfx81 is the proton density, and T1 (the spin-lattice decay time) and T2 (the spin-spin decay time) are constants of the material related to the interactions of water in cells. Typically T1 ranges from 0.2 to 1.2 seconds, while T2 ranges from 0.05 to 0.15 seconds.
By modification of the repetition and orientation of excitation pulses, an image can be made T1, T2, or proton density dominated. A proton density image shows static blood and fat as white and bone as black, while a T1 weighted image shows fat as white, blood as gray, and cerebrospinal fluid as black and T2 weighted images tend to highlight pathology since pathologic tissue tends to have longer T2 than normal tissue.
To measure spin-spin decay or relaxation time (T2) a technique referred to as the spin echo technique was developed. The spin-echo technique includes the steps of applying an RF pulse sequence at the Larmor frequency of the nuclei, whose T2 is being measured. The first RF pulse is sufficient duration to force the net magnetic moment of the nuclei to rotate 90xc2x0. This is followed by one or more RF pulses at the same Larmor frequency of sufficient duration to rotate the net magnetic field 180xc2x0. After each 180xc2x0 pulse a signal referred to as a xe2x80x9cspin-echo signalxe2x80x9d is produced. The T2 relaxation time of the nuclei is indicated by the curve drawn through the points of maximum amplitude of the echo signals received.
This technique would produce an accurate measurement of T2 if the RF magnetic field was uniform at the same Larmor frequency because then only one spin-echo signal would be generated with each 180xc2x0 pulse. Unfortunately, the RF magnetic field is not uniform. For example, some portions of the RF field may be at the Larmor frequency but other portions may be at a higher or lower frequency. It is believed that as a result of this, the inhomogeneities in the RF magnetic field produce so-called xe2x80x9cstimulated echosxe2x80x9d in addition to the primary echos.
In the present practice of the spin-echo technique for measuring T2, after the 90xc2x0 pulse, the first 180xc2x0 pulse occurs after a time period, usually called xe2x80x9ctau.xe2x80x9d Stimulated echos, however, can appear at these same times and when they do, they will be masked by and mingled with the primary echos. As a result, the degree of error in the measured T2 is unknown. Because of the errors caused by inhomogeneities in the static and RF magnetic fields of NMR machines, it is thus not possible to directly measure the T2 relaxation time (T2 RT) with a reasonable degree of certainty or accuracy.
As is also known in the art, conventional Blood Oxygenation Level Dependent (BOLD) functional MRI (fMRI) is a technique which utilizes the paramagnetic properties of deoxyhemoglobin for observing dynamic brain activity changes between baseline and active conditions.
It has been recognized in accordance with the present invention that one problem with the BOLD technique is that the mismatch between blood flow and oxygen extraction that occurs as an acute reaction to enhanced neuronal activity in BOLD does not persist under steady state conditions. Instead, regional blood flow is regulated to appropriately match perfusion with ongoing metabolic demand and deoxyhemoglobin concentration becomes constant between regions in the steady-state.
It has also been recognized in accordance with the present invention that to delineate effects of chronic drug treatment on basal brain function and to detect other conditions, it is necessary to identify possible resting or steady-state differences in regional perfusion between groups of subjects. Thus, one problem with the BOLD technique is that it cannot be used to provide insight into possible resting or steady-state differences in regional perfusion between groups of subjects, or to delineate effects of chronic drug treatment on basal brain function.
Because regional blood flow is regulated to appropriately match perfusion with ongoing metabolic demand and deoxyhemoglobin concentration becomes constant between regions in the steady-state, this indicates that regions with greater continuous activity would be perfused at a greater rate, and these regions would receive, over time, a greater volume of blood and a greater number of deoxyhemoglobin molecules per volume of tissue. Thus, there should be an augmentation in the paramagnetic properties of the region which is not detectable using the BOLD technique. Such augmentation in the paramagnetic properties of the region should be detectable as a diminished T2 relaxation time.
It has thus been further recognized in accordance with the present invention that it would be desirable to be able to identify possible resting or steady-state differences in regional perfusion between groups of subjects since such identification may provide an aid to diagnose or to directly diagnose different medical conditions.
For example, attention-deficit hyperactivity disorder (ADHD) is a highly heritable and prevalent neuropsychiatric disorder estimated to affect 6% of school-age children. Clinical hallmarks are inattention, hyperactivity and impulsivity, which often respond dramatically to treatment with methylphenidate or dextroamphetamine. Etiological theories postulate a deficit in corticostriatal circuits, particularly those components modulated by dopamine. Neuroanatomical studies have also implicated the cerebellum, a brain region involved in motor control, in the pathology of ADHD.
ADHD is typically diagnosed by observing symptoms (e.g. inattention, hyperactivity and impulsivity) in a subject. However, no physiologically measurements can be made to diagnose ADHD.
It would, therefore, be desirable to provide technique for reliably measuring the T2 RT. It would also be desirable to provide a technique for non-invasively diagnosing ADHD with MRI. It would be further desirable to reliably measure T2 RT in a particular region of interest and to use the T2 RT to aid in diagnosing and monitoring a disease. It would be still further desirable to provide a technique to measure T2 RT and to correlate changes in T2 RT to changes in blood flow.
Thus, in accordance with the present invention, an MRI system for measuring the T2 relaxation time of a sample, includes a magnet system for generating a steady, uniform magnetic field and for generating magnetic field gradients in an examination space adapted to receive the sample, a magnet controller for controlling the magnet system, an RF transmitter and receiver for generating and detecting spin resonance signals, a sampling device for sampling the detected spin resonance signals generated ;and a processor for computing a T2 relaxation time (RT) in one or more regions of interest (ROI) using median values for each of the detected spin resonance signals in the ROI.
With this particular arrangement, a system for identifying possible resting or steady-state differences in regional perfusion between groups of subjects is provided. By being able to identify resting or steady-state differences in regional perfusion between groups of subjects, the system can be used to aid in the diagnosis of or to directly diagnose different conditions in subjects. For example by reliably measuring the T2 RT in a particular region of interest in a subject it may be possible to provide a non-invasive technique for assisting in the diagnoses of a variety of diseases including but not limited to ADHD, Asperger""s syndrome, Autism, substance abuse disorders, seasonal affective disorder, childhood sexual abuse, schizophrenia, manic depression, Alzheimer""s disease, Parkinson""s disease and compulsive disorders.
In accordance with a further aspect of the present invention, a method for determining a T2 relaxation time in a sample includes the steps of (a) obtaining one or more T*1 matched axial images through a predetermined number of axial planes of the sample, (b) obtaining one or more spin echo, echoplanar image sets, with TE incremented by a predetermined value in each consecutive image set through the same axial planes used in step (a), (c) generating a map of T2 for each of the T*1 matched axial images, (d) identifying one or more regions of interest (ROI) in the images of the sample, (e) computing the median pixel intensity values in the ROI and (f) determining a T2 relaxation time from the median pixel values.
With this particular arrangement, a technique for accurately determining a T2 RT using median values in a region of interest is provided. Median values give better estimates for T2 because they are less heavily influenced by partial volume effects (e.g. having a voxel with increased CSF content does not bias the median T2 estimate in the way that the mean T2 estimate would be increased). CSF T2 values are much higher than those of brain tissue. Thus, using the median value to compute the T2 RT, a better estimate of T2 RT is provided.
In one embodiment, 32 separate spin echo images, with TE incremented by 4 msec in each consecutive image set (e.g. TE (1)=32 msec, TE (2)=36 msec, . . . TE (32)=1606 msec) are collected. Each echo is generated following a single 90xc2x0 pulse-tau 180xc2x0 pulse-tau pulse sequence. The time 2 tau is the time to echo (TE) and it is this value which is stepped. This approach results in a technique which provides relatively sensitive measurements of T2 RT. Thus this technique allows comparisons of relatively small changes in T2 RT to be made.
Importantly, by comparing T2 RT values it has been found that changes in T2 values can be correlated to changes in blood flow. Such correlation has a variety of applications. For example, if a drug administered to a patient leads to changes in blood flow, such changes can be detected by detecting changes in T2 RT. Thus the technique of the present invention can be used to actually detect changes in T2 RT which correlate with changes in blood flow. Thus, the technique of the present invention can be used to monitor changes in a patient. That is, the technique of the present invention can be used to determine or monitor in an objective sense, whether therapy improves conditions in a subject.
It should, therefore, be appreciated that in one aspect of the invention it has been recognized that changes in 12 RT can correlate with changes in blood flow. Such correlation can be made using any technique which provides a relatively sensitive measurement of T2 RT. In another aspect of the present invention, a technique for obtaining a relatively sensitive measurement of T2 RT has been found.
It has not been possible, heretofore, to detect changes in T2 RT and relate or correlate such changes in T2 RT to changes in blood flow. Moreover, the prior art indicates that it is not believed possible that changes in measured values of T2 RT could be related or correlated to changes in blood flow.
In accordance with the present invention, however, studies which included measurements of baseline T2 RT values and test T2 RT values as well as comparisons between baseline T2 RT and test T2 RT values revealed a correlation between T2 RT values and changes in blood flow of test subjects.
In accordance with a still further aspect of the present invention, apparatus for aiding the detection of ADHD in a subject includes (a) a system for exposing the subject to one or more pulses of electromagnetic energy so as to cause a time-varying response in the subject, (b) a detector for detecting in the subject a response to each of the one or more pulses of electromagnetic energy and (c) a T2 RT processor for receiving the responses and for computing a T2 relaxation time and for providing an output such that the computed T2 relaxation time can be compared with a reference T2 relaxation time such that a determination can be made as to whether the subject has ADHD.
With this particular arrangement, an apparatus for indirectly assessing blood volume in the striatum (caudate and putamen and cerebellum) under steady-state conditions and for non-invasively diagnosing ADHD) is provided. In a study using the apparatus, it was found that boys with ADHD had higher T2 relaxation time (T2 relaxometry) measures in putamen bilaterally than healthy controls. In one study eleven boys with ADHD had higher T2 relaxation times than six non-ADHD boys. The probability of this occurring by chance is 0.8%. The relaxation times correlated with the child""s capacity to sit still, and their accuracy in performing a computerized attention task. Product-moment correlation coefficients (denoted r) for each of the above activities as well as with a probability of finding this occurrence by chance (denoted p) were computed using conventional techniques. The computations of r and p resulted in values of r=xe2x88x920.73, p less than 0.001 and r=xe2x88x9274, p less than 0.001 respectively. Blinded, placebo-controlled daily treatment with methylphenidate significantly altered relaxation times in the putamen of children with ADHD (p=0.006), and dose-dependently altered relaxation times in the cerebellum in eight of the most hyperactive boys (F3,21=5.011, p=0.0089) though the magnitude and direction of the effect was strongly dependent on the child""s unmedicated activity state. No differences between ADHD children and controls in caudate or thalamus were observed, nor did relaxation times in these regions change with methylphenidate. It was discovered that ADHD symptoms may be closely tied to functional abnormalities in the putamen and cerebellum which are predominantly involved in the regulation and coordination of motoric behavior. While in this particular study the putamen was found to correspond to a brain region useful for diagnosing ADHD, it should be appreciated that other brain regions may be useful for diagnosing ADHD such as the cerebellum or frontal cortex. It should also be appreciated that the apparatus and technique of the present invention may be equally applied to other brain regions (or even other organs) and may be useful for diagnosing conditions other than ADHD.
In accordance with a yet further aspect of the present invention, a method for aiding the detection of ADHD in a subject including the steps of (a) subjecting the subject to one or more pulses of electromagnetic energy so as to cause a time-varying response in the subject, (b) computing a relaxation time T2 of the time varying response in the subject, wherein median values of the time varying response in the subject are used to compute the relaxation time T2 and providing an output which can be used to compare the detected relaxation time T2 with a reference relaxation time T2 such that a determination can be made as to whether the subject has ADHD.
With this particular arrangement, a technique for non-invasively diagnosing ADHD by indirectly assessing blood volume in the striatum (caudate and putamen) and cerebellum under steady-state conditions is provided.